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Originally published In Press as doi:10.1074/jbc.M004678200 on September 19, 2000
J. Biol. Chem., Vol. 275, Issue 49, 38275-38280, December 8, 2000
The TonE/TonEBP Pathway Mediates Tonicity-responsive Regulation
of UT-A Urea Transporter Expression*
Yushi
Nakayama §,
Tao
Peng¶,
Jeff M.
Sands , and
Serena M.
Bagnasco¶
From the Renal Division, Department of Medicine and
the ¶ Department of Pathology, Emory University School of
Medicine, Atlanta, Georgia 30322
The rat renal urea transporter UT-A
includes four isoforms. UT-A1, UT-A3, and UT-A4 are transcribed from a
single initiation site at the 5'-end of the gene; a distinct internal
initiation site is used for UT-A2 transcription. We cloned 1.3 kilobases (kb) of the 5'-flanking region upstream of the transcription
start site of UT-A1, UT-A3, and UT-A4. This region contains three CCAAT sequences but lacks a TATA motif. A tonicity-responsive enhancer (TonE)
was identified at 377bp. The 1.3-kb full fragment subcloned into pGL3
vector induced luciferase activity in Madin-Darby canine kidney cells
and in mouse inner medullary collecting duct cells in isotonic medium.
Luciferase activity was increased significantly in hypertonic medium,
whereas deletion or mutation of the TonE sequence abolished this
response. Electrophoretic mobility shift assay using the 5' UT-A TonE
sequence as DNA probe showed formation of a specific DNA-protein
complex with nuclear extracts from cells exposed to hypertonic medium
and was weakly detectable in isotonic controls. A supershift in the
mobility of the DNA-protein complex was observed with antiserum
targeted to the TonE-binding protein (TonEBP). Co-transfection with
dominant-negative TonEBP abolished the luciferase activity induced by
the UT-A 1.3-kb construct under hypertonic and isotonic conditions.
These data suggest that the TonE/TonEBP pathway mediates
tonicity-responsive transcriptional regulation of UT-A1, UT-A3, and
UT-A4 expression.
*
This work was supported in part by National Institutes of
Health Grants P01-DK50268, R01-DK41707, R01-DK53917, and Grant-in aid
96006090 from the American Heart Association. Part of this work was
presented at the Experimental Biology Meeting, April 15-18, 2000 in
San Diego, CA (Nakayama, Y., Peng, T., Sands, J. M., and Bagnasco, S. M. (2000) FASEB J. 14, A348 (abstr.)).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF214483.
§
Supported by a fellowship from the National Kidney Foundation of Georgia.
To whom correspondence should be addressed: Dept. of
Pathology, Emory University School of Medicine, WMB Rm. 7105 A, 1639 Pierce Dr., NE, Atlanta, GA 30322. Tel.: 404-727-4026; Fax:
404-727-8540; E-mail: sbagnas@emory.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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